BIOTRANSFORMATION OF FLUTICASONE: IN VITRO CHARACTERIZATION

Fluticasone propionate is a white powder with a molecular weight of Fluticasone propionate metabolism Nasal Spray, 50 mcg is an aqueous suspension of microfine fluticasone propionate for topical administration to the nasal mucosa by means of a metering, atomizing spray pump. After initial fluticasone propionate metabolism, each actuation delivers 50 mcg of online steroids uk coupon propionate in mg of formulation through the nasal adapter. Get emergency medical help if you have any of these signs of an allergic reaction: Prime FLONASE Nasal Spray before using for the first time or after a period of non-use fluticasone propionate metabolism week or more by shaking the contents well and releasing 6 sprays into the air away fluticasone propionate metabolism the face.

The purpose of this study was to investigate the metabolism and disposition of fluticasone furoate, an enhanced-affinity glucocorticoid receptor agonist, in humans.

In a two-part, open-label design study, five healthy male subjects received a p. Plasma clearance was The major circulating component identified in plasma extracts after i. Fluticasone furoate was extensively metabolized, with only trace amounts of unchanged parent compound observed in feces following either route of administration.

The predominant pathway was removal of the S -fluoromethyl carbothioate group to yield GWX M Other pathways included oxidative defluorination to yield a hydroxyl at the C6 position. There was no evidence for metabolic loss of the furoate group from fluticasone furoate or any of its metabolites. Evidence presented suggests that enterocytes have a role in the metabolism of unabsorbed fluticasone furoate.

It is a synthetic fluorinated corticosteroid that has been developed as an intranasal treatment for patients with symptoms of rhinitis. Fluticasone furoate, otherwise known as GWX, is not a salt or prodrug because the entire molecule is required for pharmacological activity.

It is well documented that topical glucocorticoids interact with many of the inflammatory pathways, and there is a large body of clinical evidence to support their use for the treatment of rhinitis, asthma, and chronic obstructive pulmonary disease Goodman and Gilman, The purpose of the present study was to investigate the metabolism and disposition of [ 14 C]fluticasone furoate after p.

These dose routes were used as surrogates for the intranasal and inhalation routes, from which the majority of the dose is likely to be swallowed. Fluticasone furoate, [ 14 C]fluticasone furoate see Fig. All of the other solvents and reagents were of analytical grade and were purchased from commercial suppliers. The structure of fluticasone furoate, with position of 14 C shown.

The solutions were at a concentration of 0. Subjects and in Vivo Study Design. All the subjects provided written informed consent before participation. The protocol was approved by the investigational center ethics committee and by the Administration of Radioactive Substances Advisory Committee, United Kingdom. The study design was an open-label two-period crossover, with a p. The subjects were in good health as shown by medical examination, clinical chemistry, hematology, and urine analysis.

The subjects were nonsmokers with no history of drug or alcohol abuse, who were taking no other medication at the time of the study, and had taken no prescribed medication within 14 days of the study commencing. All the subjects received a single p. On a separate occasion, each subject received an i. The two dosing occasions were separated by at least 28 days. Blood samples were collected via an indwelling cannula or by direct venipuncture into lithium heparin-containing polypropylene tubes.

After the start of the i. Urine samples were collected at 0 to 6, 6 to 12, and 12 to 24 h and then at h intervals up to at least h. Fecal samples were collected over h periods up to at least h postdose. Both urine and fecal collections continued beyond the h time point following i. After measurement of the total sample volume or weight as appropriate of excreta, the levels of radioactivity in samples were determined by liquid scintillation counting Beckman LS series, Bucks, UK or PerkinElmer Life and Analytical Sciences, Beaconsfield, Bucks, UK with quench correction performed by an automatic external standard ratio method, which was established using sealed 14 C standards.

Aliquots of liquid samples e. Fecal samples were homogenized with an appropriate amount of water. Aliquots of homogenized fecal material were combusted using a model oxidizer PerkinElmer Life and Analytical Sciences, Waltham, MA before radioassay by scintillation counting. The plasma had low levels of radioactivity; therefore, these samples were diluted appropriately with water, and the level of radioactivity was determined using accelerator mass spectrometry AMS.

The column was re-equilibrated following each injection. Dose analysis showed that all the p. The validation of this method was performed as detailed for the quantification of fluticasone furoate and GWX Scott et al.

An aliquot of each sample 0. Solvent A was a mixture of methanol and 10 mM ammonium formate pH 5, The column eluant was introduced into a TurboIonSpray source of a Sciex API mass spectrometer Applied Biosystems, Warrington, Cheshire, UK operated in the most sensitive ionization mode for each analyte, with the monitored fragmentation ions allowing quantification at the required sensitivity. The system was run in negative ion mode initially for 4. The appropriate mass adjustments were performed to monitor for radiolabeled material.

Determination of Metabolite Profiles. Plasma samples from individual subjects were pooled using equal volumes to produce a single representative sample per time point. No further analysis of urine samples was conducted because of the limited amount of radioactive drug-related material in urine.

The extracts were then evaporated to near dryness under a stream of nitrogen before being reconstituted in deionized water 0. Radioactive material was extracted from fecal samples using alkaline and acidified methanol as described for plasma, and the reconstituted extracts from each extraction method were combined using equal volumes before analysis by radio-HPLC.

Radiometabolite profiles were determined by analysis of appropriate aliquots of plasma and fecal extracts by radio-HPLC using on-line or off-line radiodetection. HPLC method 1 used for analysis of all the matrices. The column was re-equilibrated after each injection. HPLC column recoveries were determined on selected samples by collecting the total HPLC column eluate for the appropriate run and assaying the radioactivity to assess recovery of injected radioactivity.

Full recoveries of radioactivity were obtained from the HPLC eluant collected. HPLC method 2 used for analysis of human plasma samples. The chromatographic instrument is as listed for method 1, with the exception of a different column being used: The column was washed and re-equilibrated after each injection.

Electrospray ionization, in positive or negative modes, was used. The HPLC flow was split 1: Metabolites of fluticasone furoate were identified based on charged molecular ions and their collision-induced disassociation fragmentation. Authentic standards, where available, were used to compare chromatographic retention time to metabolites that were structurally characterized.

Supporting data obtained from metabolites identified from preclinical species or from in vitro incubations with human-derived tissue preparations were also used in the assignment of metabolite structures.

The 14 C content of human plasma, plasma extracts, and HPLC fractions was measured by AMS, which measures the radiocarbon content in a sample through separation of the isotopes of carbon present by their different mass-to-charge ratios. Before AMS analysis, the samples were graphitized via a two-step process of oxidation and reduction Vogel, A generic value of 4.

The carbon content for the HPLC fractions was deemed to be insignificant, and only the carbon content of the liquid paraffin carrier Pharmacokinetic parameters were calculated by noncompartmental methods using WinNonlin Professional version 4. Mean residence time was calculated based on the last measurable concentration. Plasma clearance and volume of distribution at steady state were calculated following i. Demographic, Safety, and Tolerability Data from Humans.

Five healthy male Caucasian subjects were enrolled and completed the study. The subjects were of a mean age of 54 years range years , a height of cm range cm , and weight of Fluticasone furoate was well tolerated, with no drug-related adverse events or clinically significant changes in vital signs observed. No concomitant medication was reported for any subject during the study. Pharmacokinetic data for fluticasone furoate, its carboxylic acid metabolite GWX, M10 , and total radioactivity are listed in Table 1.

Concentrations declined rapidly thereafter, such that they were below the limit of quantification beyond 9 h Fig. After a min i. In contrast to post-p. Mean concentrations of GWX peaked at 0. No GWX was quantifiable in plasma after i. Comparison of the AUC 0-t values for radioactivity following p. The mean bioavailability of fluticasone furoate from the oral solution comparing p.

AUC 0-t values for fluticasone furoate and normalizing for dose was considerably lower at 1. Furthermore, the mean half-life of total radioactivity at Pharmacokinetic parameters in humans for fluticasone furoate, GWX, and 14 C radioactivity in plasma. Mean pharmacokinetic parameters of fluticasone furoate, a carboxylic acid metabolite GWX, and 14 C radioactivity in plasma of healthy male subjects following a single p. The mean total recovery of radioactive drug-related material in excreta collected after i.

Radioactivity was eliminated rapidly: Mean percentage cumulative recovery of radioactivity following p. Mean plasma concentrations of fluticasone furoate, GWX, and total radioactivity as indicated on semilog plots following a p.

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